Angiotensin II Induces Skeletal Muscle Atrophy by Activating TFEB-Mediated MuRF1 Expression

Philipp Du Bois, Cristina Pablo Tortola, Doerte Lodka, Melanie Kny, Franziska Schmidt, Kunhua Song, Sibylle Schmidt, Rhonda Bassel-Duby, Eric N. Olson, Jens Fielitz

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

Rationale: Skeletal muscle wasting with accompanying cachexia is a life threatening complication in congestive heart failure. The molecular mechanisms are imperfectly understood, although an activated renin-angiotensin aldosterone system has been implicated. Angiotensin (Ang) II induces skeletal muscle atrophy in part by increased muscle-enriched E3 ubiquitin ligase muscle RING-finger-1 (MuRF1) expression, which may involve protein kinase D1 (PKD1). Objective: To elucidate the molecular mechanism of Ang II-induced skeletal muscle wasting. Methods and Results: A cDNA expression screen identified the lysosomal hydrolase-coordinating transcription factor EB (TFEB) as novel regulator of the human MuRF1 promoter. TFEB played a key role in regulating Ang II-induced skeletal muscle atrophy by transcriptional control of MuRF1 via conserved E-box elements. Inhibiting TFEB with small interfering RNA prevented Ang II-induced MuRF1 expression and atrophy. The histone deacetylase-5 (HDAC5), which was directly bound to and colocalized with TFEB, inhibited TFEB-induced MuRF1 expression. The inhibition of TFEB by HDAC5 was reversed by PKD1, which was associated with HDAC5 and mediated its nuclear export. Mice lacking PKD1 in skeletal myocytes were resistant to Ang II-induced muscle wasting. Conclusion: We propose that elevated Ang II serum concentrations, as occur in patients with congestive heart failure, could activate the PKD1/HDAC5/TFEB/MuRF1 pathway to induce skeletal muscle wasting.

Original languageEnglish (US)
Pages (from-to)424-436
Number of pages13
JournalCirculation Research
Volume117
Issue number5
DOIs
StatePublished - Aug 14 2015

Keywords

  • angiotensin II
  • gene expression regulation
  • heart failure
  • histone deacetylase 5
  • muscle RING-finger-1
  • protein kinase D
  • transcription factor EB

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Du Bois, P., Tortola, C. P., Lodka, D., Kny, M., Schmidt, F., Song, K., Schmidt, S., Bassel-Duby, R., Olson, E. N., & Fielitz, J. (2015). Angiotensin II Induces Skeletal Muscle Atrophy by Activating TFEB-Mediated MuRF1 Expression. Circulation Research, 117(5), 424-436. https://doi.org/10.1161/CIRCRESAHA.114.305393